Organonitro thioether compounds and medical uses thereof

ABSTRACT

The invention provides organonitro thioether compounds, compositions containing such compounds, isolated organonitro thioether compounds and methods for using such compounds and compositions to treat cancer in a patient. Exemplary organonitro thioether compounds described herein include 2-(3,3-dinitroazetidin-1-yl)-2-oxoethyl thioethers and variants thereof.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of and priority to U.S. ProvisionalPatent Application Ser. No. 61/544,378 filed Oct. 7, 2011, the contentsof which are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention provides organonitro thioether compounds, compositionscontaining such compounds, isolated compounds, and methods for usingsuch compounds and compositions to treat cancer in a patient.

BACKGROUND

Cancer is a significant health problem despite the many advances madefor detecting and treating this disease. Current strategies for managingcancer rely on early diagnosis and aggressive treatment. Treatmentoptions often include surgery, radiotherapy, chemotherapy, hormonetherapy, or a combination thereof. While such therapies provide abenefit to many patients, there is still a need for better therapeuticagents to treat various types of cancer.

Prostate cancer, breast cancer, and lung cancer are leading causes ofcancer-related death. Prostate cancer is the most common form of canceramong males, with an estimated incidence of 30% in men over the age of50. Moreover, clinical evidence indicates that human prostate cancer hasthe propensity to metastasize to bone, and the disease appears toprogress inevitably from androgen dependent to androgen refractorystatus, leading to increased patient mortality. Breast cancer remains aleading cause of death in women. Its cumulative risk is relatively high;certain reports indicate that approximately one in eight women areexpected to develop some type of breast cancer by age 85 in the UnitedStates. Likewise, lung cancer is a leading cause of cancer-relateddeath, and non-small cell lung cancer (NSCLC) accounts for about 80% ofthese cases. Attempts to use serum protein markers for the earlydiagnosis of lung cancer have not yielded satisfactory results forroutine screening, and newly developed early diagnostic methods usingserum DNA as a diagnostic marker await further validation.

Accordingly, there is a need for new treatment regimes to treat theseand other cancers. The present invention fulfills this need and providesother related advantages.

SUMMARY

The invention provides organonitro thioether compounds, compositionscontaining such compounds, isolated compounds, and methods for usingsuch compounds and compositions to treat cancer in a patient. Variousaspects and embodiments of the invention are described in further detailbelow.

Accordingly, one aspect of the invention provides a family oforganonitro thioether compounds embraced by Formula I for use in themethods, compositions and kits described herein, wherein Formula I isrepresented by:

or a pharmaceutically acceptable salt or solvate thereof, wherein thevariables are as defined in the detailed description. In certainembodiments, the compounds are provided in the form of an isolatedcompound of Formula I.

Another aspect of the invention provides a family of organonitrothioether compounds embraced by Formula II for use in the methods,compositions and kits described herein, wherein Formula II isrepresented by:

or a pharmaceutically acceptable salt or solvate thereof, wherein thevariables are as defined in the detailed description. In certainembodiments, the compounds are provided in the form of an isolatedcompound of Formula II.

Another aspect of the invention provides a pharmaceutical composition,comprising a pharmaceutically acceptable carrier and an organonitrothioether compound described herein, such as a compound of Formula I orII.

Another aspect of the invention provides a method of treating cancer ina patient. The method comprises administering to a patient in needthereof a therapeutically effective amount of an organonitro thioethercompound described herein, such as a compound of Formula I or II, totreat the cancer.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing SCCVII tumor volume in C3H mice that (a)received treatment with Compound 1 or (b) were not treated (i.e.,control mice), as described in Example 6.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides organonitro thioether compounds, compositionscontaining such compounds, isolated compounds, and methods for usingsuch compounds and compositions to treat cancer in a patient. Thepractice of the present invention employs, unless otherwise indicated,conventional techniques of organic chemistry, pharmacology, cellbiology, and biochemistry. Such techniques are explained in theliterature, such as in “Comprehensive Organic Synthesis” (B. M. Trost &I. Fleming, eds., 1991-1992); “Current protocols in molecular biology”(F. M. Ausubel et al., eds., 1987, and periodic updates); and “Currentprotocols in immunology” (J. E. Coligan et al., eds., 1991), each ofwhich is herein incorporated by reference in its entirety. Variousaspects of the invention are set forth below in sections; however,aspects of the invention described in one particular section are not tobe limited to any particular section.

I. DEFINITIONS

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-12,1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂alkyl,C₁-C₁₀alkyl, and C₁-C₆alkyl, respectively. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

The term “cycloalkyl” as used herein refers to a saturated cyclichydrocarbon, such as a cyclic hydrocarbon group of 3-10, or 3-6 carbonatoms, referred to herein as C₃-C₁₀cycloalkyl, and C₃-C₆cycloalkyl,respectively. Exemplary cycloalkyl groups include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term “haloalkyl” refers to an alkyl group that is substituted withat least one halogen. For example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CF₂CF₃,and the like.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup.

The term “heteroaralkyl” refers to an alkyl group substituted with aheteroaryl group.

The term “aryl” is art-recognized and refers to a carbocyclic aromaticgroup. Representative aryl groups include phenyl, naphthyl, anthracenyl,and the like. Unless specified otherwise, the aromatic ring may besubstituted at one or more ring positions with halogen, alkyl, hydroxyl,or alkoxyl. The term “aryl” also includes polycyclic ring systems havingtwo or more carbocyclic rings in which two or more carbons are common totwo adjoining rings (the rings are “fused rings”) wherein at least oneof the rings is aromatic, e.g., the other cyclic rings may becycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.

The term “heteroaryl” is art-recognized and refers to aromatic groupsthat include at least one ring heteroatom. In certain instances, aheteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representativeexamples of heteroaryl groups includes pyrrolyl, furanyl, thiophenyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl,pyrazinyl, pyridazinyl and pyrimidinyl, and the like. Unless specifiedotherwise, the heteroaryl ring may be substituted at one or more ringpositions with halogen, alkyl, hydroxyl, or alkoxyl. The term“heteroaryl” also includes polycyclic ring systems having two or morerings in which two or more carbons are common to two adjoining rings(the rings are “fused rings”) wherein at least one of the rings isheteroaromatic, e.g., the other cyclic rings may be cycloalkyls,cycloalkenyls, cycloalkynyls, and/or aryls.

The terms ortho, meta and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzenes, respectively. For example, thenames 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

As used herein, the term “heterocyclic” represents, for example, anaromatic or nonaromatic ring containing one or more heteroatoms. Theheteroatoms can be the same or different from each other. Examples ofheteroatoms include, but are not limited to nitrogen, oxygen and sulfur.Aromatic and nonaromatic heterocyclic rings are well-known in the art.Some nonlimiting examples of aromatic heterocyclic rings includepyridine, pyrimidine, indole, purine, quinoline and isoquinoline.Nonlimiting examples of nonaromatic heterocyclic compounds includepiperidine, piperazine, morpholine, pyrrolidine and pyrazolidine.Examples of oxygen containing heterocyclic rings include, but are notlimited to furan, oxirane, 2H-pyran, 4H-pyran, 2H-chromene, andbenzofuran. Examples of sulfur-containing heterocyclic rings include,but are not limited to, thiophene, benzothiophene, and parathiazine.Examples of nitrogen containing rings include, but are not limited to,pyrrole, pyrrolidine, pyrazole, pyrazolidine, imidazole, imidazoline,imidazolidine, pyridine, piperidine, pyrazine, piperazine, pyrimidine,indole, purine, benzimidazole, quinoline, isoquinoline, triazole, andtriazine. Examples of heterocyclic rings containing two differentheteroatoms include, but are not limited to, phenothiazine, morpholine,parathiazine, oxazine, oxazole, thiazine, and thiazole. The heterocyclicring is optionally further substituted at one or more ring positionswith, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,carboxylic acid, —C(O)alkyl, —CO₂alkyl, carbonyl, carboxyl, alkylthio,sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,heterocyclyl, aryl or heteroaryl moieties, —CF₃, —CN, or the like.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety represented by thegeneral formula —N(R⁵⁰)(R⁵¹), wherein R⁵⁰ and R⁵¹ each independentlyrepresent hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl,aralkyl, or —(CH₂)_(m)—R⁶¹; or R⁵⁰ and R⁵¹, taken together with the Natom to which they are attached complete a heterocycle having from 4 to8 atoms in the ring structure; R⁶¹ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle or a polycycle; and m is zero or an integerin the range of 1 to 8. In certain embodiments, R⁵⁰ and R⁵¹ eachindependently represent hydrogen, alkyl, alkenyl, or —(CH)_(m)—R⁶¹.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl,—O—(CH₂)_(m)—R₆₁, where m and R₆₁ are described above.

Certain compounds contained in compositions of the present invention mayexist in particular geometric or stereoisomeric forms. The presentinvention contemplates all such compounds, including cis- andtrans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers,(L)-isomers, the racemic mixtures thereof, and other mixtures thereof,as falling within the scope of the invention. Additional asymmetriccarbon atoms may be present in a substituent such as an alkyl group. Allsuch isomers, as well as mixtures thereof, are intended to be includedin this invention. It is understood that unless specified otherwise(e.g., using indicators of stereochemical configuration, such as wedgeand/or dashed bonds), the chemical formulae encompass all geometric andstereoisomeric forms, including mixtures of geometric and/orstereoisomeric forms.

If, for instance, a particular enantiomer of a compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

As used herein, the terms “subject” and “patient” refer to organisms tobe treated by the methods of the present invention. Such organisms arepreferably mammals (e.g., murines, simians, equines, bovines, porcines,canines, felines, and the like), and more preferably humans. The term“non-anemic patient” refers to a patient that does not suffer fromanemia.

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. An effective amount can beadministered in one or more administrations, applications or dosages andis not intended to be limited to a particular formulation oradministration mute. As used herein, the term “treating” includes anyeffect, e.g., lessening, reducing, modulating, ameliorating oreliminating, that results in the improvement of the condition, disease,disorder, and the like, or ameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants. (See e.g., Martin.Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton,Pa. [1975]).

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metals (e.g.,sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄⁺ (wherein W is a C₁₋₄ alkyl group), and the like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

The term “ABDNAZ” is art-recognized and refers to the followingcompound:

The abbreviation “TFA” is art-recognized and refers to trifluoroaceticacid.

As used herein, the term “isolated” refers to material that is removedfrom its original environment (e.g., the natural environment if it isnaturally occurring).

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

II. ORGANONITRO THIOETHER COMPOUNDS FOR USE IN THE METHODS,COMPOSITIONS, AND KITS DESCRIBED HEREIN

One aspect of the invention provides organonitro thioether compounds foruse in the methods, compositions and kits described herein. In certainembodiments, the organonitro compound is a compound embraced by FormulaI:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

A¹ is N or —C(R⁵)—;

A² is —C(O)— or —(C(R⁶)₂)_(x)C(O)(C(R⁶)₂)_(x)—;

R¹ is C₁-C₅alkyl;

R² and R³ each represent independently for each occurrence hydrogen orC₁-C₅alkyl; or R² and R³ are taken together with the carbon atom towhich they are attached to form a carbocyclic ring;

R⁴ is C₁-C₅alkyl substituted with one X¹ group and one X² group; whereinX¹ is —N(R⁷)(R⁸), —N(R⁷)C(O)—C₁-C₅alkyl, —N(R⁷)C(O)—C₃-C₇cycloalkyl,—N(R⁷)C(O)-aryl, —N(R⁷)C(O)-aralkyl, or—N(R⁷)C(O)—(C₁-C₅alkylene)-C(H)[N(R⁷)(R⁸)]—CO₂R⁹; and X² is —CO₂R¹⁰ or—C(O)N(R⁷)—(C₁-C₅alkylene)-CO₂R¹⁰;

R⁵ is hydrogen or C₁-C₅alkyl;

R⁶ represents independently for each occurrence C₁-C₆alkyl,C₁-C₅haloalkyl, aryl, or aralkyl;

R⁷ and R⁸ each represent independently for each occurrence hydrogen orC₁-C₅alkyl; or R⁷ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocyclic ring;

R⁹ and R¹⁰ each represent independently hydrogen, C₁-C₅alkyl,C₃-C₇cycloalkyl, aryl, or aralkyl;

n, p, and t are independently 1, 2, or 3; and

m and x each represent independently for each occurrence 0, 1, 2, or 3.

In certain embodiments, A¹ is N. In certain embodiments, A² is —C(O)—.

In certain embodiments, R² and R³ are hydrogen.

In certain embodiments, m is 0. In certain embodiments, n is 2. Incertain other embodiments, n is 1. In certain embodiments, t is 1.

In certain embodiments, R⁴ is —CH₂C(H)(X¹)X². In certain otherembodiments, R⁴

In certain other embodiments, R⁴ is

In certain embodiments, X¹ is —N(R⁷)(R⁸), —N(R⁷)C(O)—C₁-C₅alkyl, or—N(R⁷)C(O)—(C₁-C₅alkylene)-C(H)[N(R⁷)(R⁸)]—CO₂R⁹. In certain otherembodiments, X¹ is —NH₂, —N(H)C(O)CH₂, or —N(H)C(O)CH₂CH₂C(H)(NH₂)—CO₂H;and X² is —CO₂H, —CO₂Me, or —C(O)N(H)CH₂CO₂H. In certain otherembodiments, X¹ is —NH₂ or —N(H)C(O)CH₂CH₂C(H)(NH₂)—CO₂H; and X² is—CO₂H or —C(O)N(H)CH₂CO₂H.

The description above describes multiple embodiments relating tocompounds of Formula I. The patent application specifically contemplatesall combinations of the embodiments. For example, the inventioncontemplates a compound of Formula I wherein A¹ is N, A² is —C(O)—, R²and R³ are hydrogen, m is 0, n is 2, t is 1, and R⁴ is —CH₂C(H)(X¹)X².Further, to illustrate, the invention contemplates a compound of FormulaI wherein A¹ is N, A² is —C(O)—, R² and R³ are hydrogen, m is 0, n is 1,t is 1, and R⁴ is —CH₂C(H)(X¹)X².

In certain embodiments, the compound is a compound of Formula I-A:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

A¹ is N or C(H);

R¹ represents independently for each occurrence hydrogen or methyl;

R⁴ is C₁-C₅alkyl substituted with one X¹ group and one X² group; whereinX¹ is —NH₂, —N(H)C(O)—C₁-C₅alkyl, or—N(H)C(O)—(C₁-C₅alkylene)-C(H)(NH₂)—CO₂H; and X² is —CO₂H,—CO₂—C₁-C₅alkyl, or —C(O)N(H)CH₂CO₂H; and

p represents independently for each occurrence 1 or 2.

In certain embodiments, R⁴ is —CH₂C(H)(X¹)X². In certain otherembodiments, wherein R⁴ is

In certain embodiments, X¹ is —NH₂, —N(H)C(O)CH₃, or—N(H)C(O)CH₂CH₂C(H)(NH₂)—CO₂H; and X² is —CO₂H, —CO₂Me, or—C(O)N(I)CH₂CO₂H. In certain embodiments, X¹ is —NH₂ or—N(H)C(O)CH₂CH₂C(H)(NH₂)—CO₂H; and X² is —CO₂H or —C(O)N(H)CH₂CO₂H.

In certain embodiments, the organonitro compound is represented by

wherein R⁴ is

The description above describes multiple embodiments relating tocompounds of Formula I-A. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates a compound of Formula I-A wherein A¹ is N, R¹ ishydrogen, R⁴ is —CH₂C(H)(X¹)X², and p is 1.

In certain embodiments, the compound is a compound of Formula I-B:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

A¹ is N or C(H);

R¹ represents independently for each occurrence hydrogen or methyl;

R⁴ is C₁-C₅alkyl substituted with one X¹ group and one X² group; whereinX¹ is —NH₂, —N(H)C(O)—C₁-C₅alkyl or—N(H)C(O)—(C₁-C₅alkylene)-C(H)(NH₂)—CO₂H; and X² is —CO₂H,—CO₂—C₁-C₅alkyl, or —C(O)N(H)CH₂CO₂H; and

p represents independently for each occurrence 1 or 2.

In certain embodiments, R⁴ is —CH₂C(H)(X¹)X¹. In certain otherembodiments, wherein R⁴ is

The description above describes multiple embodiments relating tocompounds of Formula I-B. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates a compound of Formula I-B wherein A¹ is N, R¹ ishydrogen, R⁴ is —CH₂C(H)(X¹)X², and p is 1.

In certain embodiments, the compound is one of the following:

In certain embodiments, the compound is one of the foregoing or apharmaceutically acceptable salt thereof.

In certain other embodiments, the organonitro compound is a compoundembraced by Formula II:

or a pharmaceutically acceptable salt or solvate thereof: wherein:

A¹ is —N(R⁵)— or —C(R²)(R³)—;

A² is —C(O)— or —(C(R⁶)₂)_(x)C(O)(C(R⁶)₂)_(x)—;

R¹ is C₁-C₅alkyl or C₃-C₇cycloalkyl;

R² and R³ each represent independently for each occurrence hydrogen orC₁-C₅alkyl; or R² and R³ are taken together with the carbon atom towhich they are attached to form a carbocyclic ring;

R⁴ is C₁-C₅alkyl substituted with one X¹ group and one X² group; whereinX¹ is —N(R⁷)(R⁸), —N(R⁷)C(O)—C₁-C₅alkyl, —N(R⁷)C(O)—C₃-C₇cycloalkyl,—N(R⁷)C(O)-aryl, —N(R⁷)C(O)-aralkyl, or—N(R⁷)C(O)—(C₁-C₅alkylene)-C(H)[N(R⁷)(R⁸)]—CO₂R⁹; and X² is —CO₂R¹⁰ or—C(O)N(R⁷)—(C₁-C₅alkylene)-CO₂R¹⁰;

R⁵ is hydrogen or C₁-C₅alkyl;

R⁶ represents independently for each occurrence C₁-C₅alkyl,C₁-C₅haloalkyl, aryl, or aralkyl;

R⁷ and R⁸ each represent independently for each occurrence hydrogen orC₁-C₅alkyl; or R⁷ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocyclic ring;

R⁹ and R¹⁰ each represent independently hydrogen, C₁-C₅alkyl,C₃-C₇cycloalkyl, aryl, or aralkyl;

t and v are independently 1, 2, or 3; and

x represents independently for each occurrence 0, 1, 2, or 3.

In certain embodiments, A¹ is N. In certain embodiments, A² is —C(O)—.

In certain embodiments, R² and R³ are hydrogen.

In certain embodiments, m is 0. In certain embodiments, n is 2. Incertain other embodiments, n is 1. In certain embodiments, wherein tis 1. In certain embodiments, wherein v is 1.

In certain embodiments, R⁴ is —CH₂C(H)(X¹)X². In certain otherembodiments, R⁴

In certain other embodiments, R⁴ is

In certain embodiments, X¹ is —N(R⁷)(R⁸), —N(R⁷)C(O)—C₁-C₅alkyl, or—N(R⁷)C(O)—(C₁-C₅alkylene)-C(H)[N(R⁷)(R⁸)]—CO₂R⁹. In certain otherembodiments, X¹ is —NH₂, —N(H)C(O)CH₂, or —N(H)C(O)CH₂CH₂C(H)(NH₂)—CO₂H;and X² is —CO₂H, —CO₂Me, or —C(O)N(H)CH₂CO₂H. In certain otherembodiments, X¹ is —NH₂ or —N(H)C(O)CH₂CH₂C(H)(NH₂)—CO₂H; and X² is—CO₂H or —C(O)N(H)CH₂CO₂H.

The description above describes multiple embodiments relating tocompounds of Formula II. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates a compound of Formula II wherein A¹ is N, A² is—C(O)—, R² and R³ are hydrogen, t is 1, v is 1, and R⁴ is—CH₂C(H)(X¹)X².

In certain embodiments, the invention provides compounds of Formula I inisolated form. In another embodiment, the isolated compound of Formula Iis substantially pure (that is having a purity of at least about 70%,80%, 90%, 95%, or 99% by weight).

In certain embodiments, the invention provides compounds of Formula I-Ain isolated form. In another embodiment, the isolated compound ofFormula I-A is substantially pure (that is having a purity of at leastabout 70%, 80%, 90%, 95%, or 99% by weight). For example, in certainembodiments, the isolated compound may be one of the following isolatedcompounds:

In certain embodiments, the isolated compound is one of the foregoing ora pharmaceutically acceptable salt thereof.

In certain other embodiments, the invention provides compounds ofFormula II in isolated form. In another embodiment, the isolatedcompound of Formula I is substantially pure (that is having a purity ofat least about 70%, 80%, 90%, 95%, or 99% by weight).

In certain other embodiments, the compound is one of the compoundslisted in Tables 1, 2, or 3 below or a pharmaceutically acceptable saltor solvate thereof.

TABLE 1

Compound No. X Y I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

TABLE 2

Compound No. X A Y II-1

—CH₂C(O)—

II-2

—CH₂C(O)—

II-3

—CH₂C(O)—

II-4

—CH₂C(O)—

II-5

—C(O)CH₂CH₂—

II-6

—C(O)CH₂CH₂—

II-7

—C(O)CH₂CH₂—

II-8

—C(O)CH₂CH₂—

II-9

—CH₂—

II-10

—CH₂—

II-11

—CH₂—

II-12

—CH₂—

II-13

—CH₂C(O)—

II-14

—CH₂C(O)—

II-15

—CH₂C(O)—

II-16

—C(O)CH₂CH₂—

II-17

—C(O)CH₂CH₂—

II-18

—C(O)CH₂CH₂—

II-19

—CH₂—

II-20

—CH₂—

II-21

—CH₂—

II-22

—CH₂C(O)—

II-23

—C(O)CH₂CH₂—

II-24

—CH₂—

II-25

—CH₂C(O)—

II-26

—C(O)CH₂CH₂—

II-27

—CH₂—

II-28

—CH₂C(O)—

II-29

—CH₂C(O)—

II-30

—CH₂C(O)—

II-31

—CH₂C(O)—

II-32

—CH₂C(O)—

II-33

—C(O)CH₂CH₂—

II-34

—CH₂—

II-35

—CH₂C(O)—

TABLE 3

Compound No. X Y Z III-1

—N(H)CH₂— methyl III-2

—N(H)CH₂— methyl III-3

—N(H)CH₂— ethyl III-4

—N(H)CH₂— n-pentyl III-5

—N(H)CH₂— hydrogen III-6

—N(H)CH₂CH₂— methyl III-7

—N(H)(CH₂)₄— methyl III-8

—N(CH₃)CH₂— methyl III-9

—N(CH₃)(CH₂)₃— methyl III-10

—N(H)C(CH₃(H)— methyl III-11

—N(H)C(CH₃)(H)CH₂— methyl III-12

—CH₂— methyl III-13

—(CH₂)₂— methyl III-14

—CH₂— ethyl III-15

—(CH₂)₄— isopropyl III-16

—(CH₂)₂— n-pentyl III-17

—CH₂— hydrogen III-18

—CH₂CH₂C(CH₃)₂— methyl III-19

—CH₂C(CH₃)₂CH₂— methyl III-20

—N(H)CH₂— methyl III-21

—N(H)CH₂— ethyl III-22

—N(CH₃)CH₂— methyl III-23

—(CH₂)₂— methyl III-24

—N(H)CH₂— methyl III-25

—N(H)CH₂— ethyl III-26

—N(CH₃)CH₂— methyl III-27

—(CH₂)₂— methyl III-28

—N(H)CH₂— methyl III-29

—N(CH₃)CH₂— methyl III-30

—N(H)CH₂— methyl III-31

—N(CH₃)CH₂— methyl III-32

—N(H)CH₂— methyl III-33

—N(CH₃)CH₂— methyl III-34

—N(H)CH₂— methyl III-35

—N(CH₃)CH₂— methyl III-36

—(CH₂)₂— methyl III-37

—N(H)CH₂— n-pentyl III-38

—N(CH₃)CH₂— methyl III-39

—N(H)CH₂CH₂— ethyl III-40

—N(H)CH₂— methyl III-41

—N(H)CH₂— methyl

Methods for preparing compounds described herein are illustrated in thefollowing synthetic schemes. These schemes are given for the purpose ofillustrating the invention, and should not be regarded in any manner aslimiting the scope or the spirit of the invention. Starting materialsshown in the schemes can be obtained from commercial sources or can beprepared based on procedures described in the literature.

The synthetic route illustrated in Scheme 1 depicts a general method forpreparing cyclic geminal di-nitro compounds. In the first step, chloroepoxide A1 is reacted with t-butylamine to provide hydroxy heterocycliccompound B1. Mesylation of the hydroxyl group of heterocyclic compoundB1 with methylsulfonyl chloride gives mesylate C1, which upon reactingwith NaNO₂ generates cyclic mono-nitro compound D1. Further nitration ofcompound D1 can be carried out using NaNO₂ in the presence of Na₂S₂O₈and K₃Fe(CN)₆ to provide geminal di-nitro heterocyclic compound E1. Athree-step procedure provides final compound G1, which involves reactionof compound E1 with boron trifluoride etherate, acylation with acetylbromide F, and thiolation to provide compound G1. Further description ofrelated synthetic procedures are described in, for example, Archibald etal. in J. Org. Chem. 1990, 55, 2920-2924; U.S. Pat. No. 7,507,842; andJ. P. Agrawal, R. D. Hodgson, Organic Chemistry of Explosives, Wiley &Sons, England, 2007 and references cited therein.

This synthetic procedure illustrated in Scheme 1 and described above iscontemplated to be applicable to preparing compounds having varioussubstituents at the R₁, R₂, R₃ and R₄ positions. If a particular epoxidecompound embraced by A1 should contain a functional group sensitive toone or more of the synthetic transformations in Scheme 1, then standardprotecting group strategies are contemplated to be applied. For furtherdescription of protecting group strategies and procedures, see, forexample, Greene, T. W.; Wuts, P.G.M. Protective Groups in OrganicSynthesis, 2^(nd) ed.; Wiley, New York, 1991.

Scheme 2 illustrates a more specific embodiment of the synthetic routeshown in Scheme 1 when m is 0. In the first step, epoxide A2 is reactedwith t-butylamine to provide hydroxyl azetidine B2. Mesylation of thehydroxyl group of azetidine B2 with methylsulfonyl chloride givesazetidine mesylate C2, which upon reacting with NaNO₂ generatesmono-nitro azetidine D2. Further nitration of mono-nitro azetidnine D2with NaNO₂ in the presence of Na₂S₂O₈ and K₃Fe(CN)₆ furnishes thegeminal di-nitro azetidine E2. A three-step procedure provides di-nitroazetidine G2, which involves reaction of compound E2 with borontrifluoride etherate, acylation with acetyl bromide F, and thiolation toprovide di-nitro azetidine G2. This synthetic procedure is contemplatedto be applicable to preparing compounds having various substituents atthe R₁, R₂, R₃ and R₄ positions. If a particular epoxide compoundembraced by A2 should contain a functional group sensitive to one ormore of the synthetic transformations in Scheme 2, then standardprotecting group strategies are contemplated to be applied. For furtherdescription of protecting group strategies and procedures, see, forexample, Greene, T.W.; Wuts, P.G.M. Protective Groups in OrganicSynthesis, 2^(nd) ed.; Wiley, New York, 1991. Furthermore, mono-nitrocompounds can be prepared by treating mono-nitro compound D2 with aLewis Acid (e.g., boron trifluoride etherate) and acetyl bromidecompound F (e.g., from Scheme 2) to provide the desired mono-nitroproduct.

Scheme 3 illustrates another more particular embodiment of the syntheticroute shown in Scheme 1 when both R₁ and R₂ are hydrogen and m is 0. Inthe first step, commercially available epichlorohydrin A3 is reactedwith t-butylamine to provide hydroxyl azetidine B3. Mesylation of thehydroxyl group of azetidine B3 with methylsulfonyl chloride givesazetidine mesylate C3, which upon reacting with NaNO₂ generatesmono-nitro azetidine D3. Further nitration of mono-nitro azetidine D3with NaNO₂ in the presence of Na₂S₂O₈ and K₃Fe(CN)₆ furnishes thegeminal di-nitro azetidine E3. A three-step procedure provides di-nitroazetidine F3, which involves reaction of compound E3 with borontrifluoride etherate, acylation with acetyl bromide, and thiolation toprovide di-nitro azetidine F3. Further description of related syntheticprocedures are described in, for example, Archibald et al. in J. Org.Chem. 1990, 55, 2920-2924; U.S. Pat. No. 7,507,842; and J. P. Agrawal,R. D. Hodgson. Organic Chemistry of Explosives, Wiley & Sons, England,2007 and references cited therein. Furthermore, mono-nitro compounds canbe prepared by treating mono-nitro compound D3 with a Lewis Acid (e.g.,boron trifluoride etherate) and acetyl bromide compound F to provide thedesired bromo mono-nitro product, which may be subjected todebromination procedures to replace the bromine atom with a hydrogen.

Scheme 4 illustrates an alternative exemplary procedure for preparingcyclic geminal di-nitro compounds. In the first step, heterocycliccompound A4 is reacted with an oxidant, such as pyridinium dichromate(PDC), to provide heterocyclic ketone B4. Reaction of ketone B4 withhydroxylamine gives heterocyclic oxime C4, which upon reaction withN-bromosuccinimide (NBS) produces bromo nitro compound D4. Reaction ofcompound D4 with NaBH₄ furnishes mono-nitro compound E4. Reaction ofmono-nitro compound E4 with NaNO₂ in the presence of Na₂S₂O₈ andK₃Fe(CN)₆ provides geminal di-nitro heterocyclic compound F4. Athree-step procedure provides cyclic geminal di-nitro G4, which involvesreaction of compound F4 with a deprotecting agent, acylation with acetylbromide compound F, and thiolation to provide cyclic geminal di-nitroproduct G4. Further description of related synthetic procedures aredescribed in, for example, Archibald et al. in J. Org. Chem. 1990, 55,2920-2924; U.S. Pat. No. 7,507,842; and J. P. Agrawal, R. D. Hodgson,Organic Chemistry of Explosives, Wiley & Sons, England, 2007 andreferences cited therein. Furthermore, mono-nitro compounds can beprepared by treating mono-nitro compound D4 with a deprotecting agentand acetyl bromide compound F to provide the desired bromo mono-nitroproduct, which may be subjected to debromination procedures to replacethe bromine atom with a hydrogen.

Scheme 5 illustrates yet another exemplary procedure for preparingcyclic geminal di-nitro compounds with initial steps different fromthose shown in Scheme 4. In the first step, heterocyclic compound A4 isreacted with methylsulfonyl chloride to provide heterocyclic mesylateB5. Reaction of mesylate B5 with NaNO₂ gives mono-nitro compound E4.Nitration of compound E4 with NaNO₂ in the presence of Na₂S₂O₈ andK₃Fe(CN)₆ provides geminal di-nitro compound F4. A three-step procedureprovides di-nitro compound G4, which involves reaction of compound F4with a deprotecting agent, acylation with acetyl bromide compound F, andthiolation to provide di-nitro compound G4. Further description ofrelated synthetic procedures are described in, for example, Archibald etal. in J. Org. Chem. 1990, 55, 2920-2924; U.S. Pat. No. 7,507,842; andJ. P. Agrawal, R. D. Hodgson, Organic Chemistry of Explosives, Wiley &Sons, England, 2007 and references cited therein. Furthermore,mono-nitro compounds can be prepared by treating mono-nitro compound E4with a deprotecting agent and acetyl bromide compound F to provide thedesired mono-nitro product.

The synthetic route illustrated in Scheme 6 depicts an exemplary methodfor preparing cyclic vicinal di-nitro compounds. In the first step,cycloalkene A6 is reacted with N₂O₄ to provide vicinal di-nitro compoundB6. A three-step procedure provides vicinal di-nitro product C6, whichinvolves reaction of compound B6 with a deprotecting agent, acylationwith acetyl bromide compound F, and thiolation to provide vicinaldi-nitro compound C6. Further description of related syntheticprocedures are described in, for example, Archibald et al. in J. Org.Chem. 1990, 55, 2920-2924; U.S. Pat. No. 7,507,842; and J. P. Agrawal,R. D. Hodgson. Organic Chemistry of Explosives, Wiley & Sons, England,2007 and references cited therein. This synthetic procedure iscontemplated to be applicable to preparing compounds having varioussubstituents at the R₁, R₂, R₃ and R₄ positions. If a particularcycloalkene compound embraced by A6 should contain a functional groupsensitive to one or more of the synthetic transformations in Scheme 6,then standard protecting group strategies are contemplated to beapplied. For further description of protecting group strategies andprocedures, see, for example, Greene, T.W.; Wuts, P.G.M. ProtectiveGroups in Organic Synthesis, 2^(nd) ed.; Wiley, New York, 1991.

The synthetic route illustrated in Scheme 7 depicts a general method forpreparing cyclic mono-nitro compounds. In the first step, chloro epoxideA7 is reacted with t-butylamine to provide hydroxy heterocyclic compoundB7. Mesylation of the hydroxyl group of heterocyclic compound B7 withmethylsulfonyl chloride gives mesylate C7 which upon reacting with NaNO₂generates cyclic mono-nitro compound D7. A three-step procedure providescompound G7, which involves reaction of compound D7 with borontrifluoride etherate, acylation with acetyl bromide compound F, andthiolation to provide compound G7. Further description of relatedsynthetic procedures are described in, for example, Archibald et al. inJ. Org. Chem. 1990, 55, 2920-2924; U.S. Pat. No. 7,507,842; and J. P.Agrawal, R. D. Hodgson, Organic Chemistry of Explosives, Wiley & Sons,England, 2007 and references cited therein. This synthetic procedureillustrated in Scheme 7 is contemplated to be applicable to preparingcompounds having various substituents at the R₁, R₂, R₃ and R₄positions. If a particular epoxide compound embraced by A7 shouldcontain a functional group sensitive to one or more of the synthetictransformations in Scheme 7, then standard protecting group strategiesare contemplated to be applied. For further description of protectinggroup strategies and procedures, see, for example, Greene, T.W.; Wuts,P.G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley, NewYork, 1991.

The synthetic routes described above can be modified to preparecompounds having an alkyl halide attached to the ring nitrogen atom.Exemplary synthetic procedures for preparing such compounds includereducing the amide group of compound G1-G4, G7, and C6 to an amine.Alternatively, compound F used in the procedures above could be replacedwith an appropriately protected alkylhalide, such that after thealkylation reaction, the protected alkyl group attached to the ringnitrogen atom is deprotected and converted to an alkyl chloride orbromide.

Scheme 8 depicts another exemplary method for preparing cyclicmono-nitro and di-nitro compounds. Reaction of ketone B8 withhydroxylamine gives heterocyclic hydroxylamine C8, which upon reactionwith N-bromosuccinimide (NBS) produces bromo nitro compound D8. Reactionof compound D8 with NaBH₄ furnishes mono-nitro compound E8. The hydroxylprotecting group (P, which may be, for example, atert-butyldimethylsilyl group) and the 1,2-dihydroxyethane protectinggroup are removed using standard deprotection conditions. Exemplarydeprotection conditions for removing a tert-butyldimethyl silyl groupinclude addition of tetra-n-butylammonium fluoride. Exemplarydeprotection conditions for removing a 1,2-dihydroxyethane protectinggroup include addition of hydrochloric acid and water. Hydroxy-ketone F8can be converted to α-bromo ketone G8 by first reacting compound F8 withmethanesulfonyl chloride to form a mesylate and then adding sodiumbromide to form α-bromo ketone G8.

Di-nitro compounds can be prepared by reacting mono-nitro compound E8with NaNO₂ in the presence of Na₂S₂Os and K₃Fe(CN)₆ to provide geminaldi-nitro heterocyclic compound H8. The hydroxyl protecting group (P,which may be, for example, a tert-butyldimethyl silyl group) and the1,2-dihydroxyethane protecting group of compound H8 may be removed usingstandard deprotection conditions. Exemplary deprotection conditions forremoving a tert-butyldimethyl silyl group include addition oftetra-n-butylammonium fluoride. Exemplary deprotection conditions forremoving a 1,2-dihydroxyethane protecting group include addition ofhydrochloric acid and water. Hydroxy-ketone I8 can be converted toca-bromo ketone J8 by first reacting compound I8 with methanesulfonylchloride to form a mesylate and then adding sodium bromide to form anα-bromo ketone. Thiolation of the α-bromo ketone provides the desiredproduct J8. Further description of related synthetic procedures aredescribed in, for example, Archibald et al. in J. Org. Chem. 1990, 55,2920-2924 and J. P. Agrawal, R. D. Hodgson, Organic Chemistry ofExplosives, Wiley & Sons, England, 2007 and references cited therein.

Scheme 9 illustrates an exemplary procedure for preparing acyclicgeminal di-nitro compounds. In the first step, protected amino alcoholA9 is reacted with methylsulfonyl chloride to provide mesylate B9.Reaction of mesylate B9 with NaNO₂ gives mono-nitro compound E9.Nitration of compound E9 with NaNO₂ in the presence of Na₂S₂O₈ andK₃Fe(CN)₆ provides geminal di-nitro compound F9. A three-step procedureprovides the desired di-nitro product G9, which involves reaction ofcompound F9 with a deprotecting agent, acylation with acetyl bromidecompound F, and thiolation to provide di-nitro product G9. Furtherdescription of related synthetic procedures are described in, forexample, Archibald et al. in J. Org. Chem. 1990, 55, 2920-2924; U.S.Pat. No. 7,507,842; and J. P. Agrawal, R. D. Hodgson, Organic Chemistryof Explosives, Wiley & Sons, England, 2007 and references cited therein.

Scheme 10 illustrates an alternative procedure for preparing mono-nitrocompounds. Reaction of dinitro compound A10 with thiol compound B10provides mono-nitro compound C10. The reaction can be performed at roomtemperature, or the reaction mixture can be heated to achieve atemperature higher than room temperature. One or more equivalents ofthiol B10 may be used, relative to the amount of dinitro compound A10.One exemplary thiol B10 that can be used in the procedure is cysteine. Amore specific illustration of this synthetic procedure is the reactionof dinitro compound A10′ with cysteine (B10′) to provide mono-nitrocompound C10′.

III. THERAPEUTIC APPLICATIONS

The invention provides methods of treating various medical disorders,such as cancer, using the organonitro thioether compounds andpharmaceutical compositions described herein. Treatment methods includethe use of organonitro thioether compounds described herein asstand-alone chemotherapeutic agents, as radiation sensitizers, and/or aspart of a combination therapy with another therapeutic agent. Althoughnot wishing to be bound by a particular theory, it is understood thatorganonitro thioether compounds described herein can release reactivefree radicals that are cytotoxic to cancer cells.

Methods of Treating Medical Disorders

One aspect of the invention provides a method of treating cancer in apatient. The method comprises administering to a patient in need thereofa therapeutically effective amount of an organonitro thioether compounddescribed herein, such as a compound of Formula I or II, which asdescribed above, Formula I is represented by:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

A¹ is N or —C(R⁵)—;

A² is —C(O)— or —(C(R⁶)₂)_(x)C(O)(C(R⁶)₂)_(x);

R¹ is C₁-C₅alkyl;

R² and R³ each represent independently for each occurrence hydrogen orC₁-C₅alkyl; or R² and R³ are taken together with the carbon atom towhich they are attached to form a carbocyclic ring;

R⁴ is C₁-C₅alkyl substituted with one X¹ group and one X² group; whereinX¹ is —N(R⁷)(R⁸), —N(R⁷)C(O)—C₁-C₅alkyl, —N(R⁷)C(O)—C₃-C₇cycloalkyl,—N(R⁷)C(O)-aryl, —N(R⁷)C(O)-aralkyl, or—N(R⁷)C(O)—(C₁-C₅alkylene)-C(H)[N(R⁷)(R⁸)]—CO₂R⁹; and X² is —CO₂R¹⁰ or—C(O)N(R⁷)—(C₁-C₅alkylene)-CO₂R¹⁰;

R⁵ is hydrogen or C₁-C₅alkyl;

R⁶ represents independently for each occurrence C₁-C₆alkyl,C₁-C₅haloalkyl, aryl, or aralkyl;

R⁷ and R⁸ each represent independently for each occurrence hydrogen orC₁-C₅alkyl; or R⁷ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocyclic ring;

R⁹ and R¹⁰ each represent independently hydrogen, C₁-C₅alkyl,C₃-C₇cycloalkyl, aryl, or aralkyl;

n, p, and t are independently 1, 2, or 3; and

m and x each represent independently for each occurrence 0, 1, 2, or 3;and Formula II is represented by:

or a pharmaceutically acceptable salt or solvate thereof: wherein:

A¹ is —N(R⁵)— or —C(R²)(R³)—;

A² is —C(O)— or —(C(R⁶)₂)_(x)C(O)(C(R⁶)₂)_(x)—;

R¹ is C₁-C₅alkyl or C₃-C₇cycloalkyl;

R² and R³ each represent independently for each occurrence hydrogen orC₁-C₅alkyl; or R² and R³ are taken together with the carbon atom towhich they are attached to form a carbocyclic ring;

R⁴ is C₁-C₅alkyl substituted with one X¹ group and one X² group; whereinX¹ is —N(R⁷)(R⁸), —N(R⁷)C(O)—C₁-C₅alkyl, —N(R⁷)C(O)—C₃-C₇cycloalkyl,—N(R⁷)C(O)-aryl, —N(R⁷)C(O)-aralkyl, or—N(R⁷)C(O)—(C₁-C₅alkylene)-C(H)[N(R⁷)(R⁸)]—CO₂R⁹; and X² is —CO₂R¹⁰ or—C(O)N(R⁷)—(C₁-C₅alkylene)-CO₂R¹⁰;

R⁵ is hydrogen or C₁-C₅alkyl;

R⁶ represents independently for each occurrence C₁-C₅alkyl,C₁-C₅haloalkyl, aryl, or aralkyl;

R⁷ and R⁸ each represent independently for each occurrence hydrogen orC₁-C₅alkyl; or R⁷ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocyclic ring;

R⁹ and R¹⁰ each represent independently hydrogen, C₁-C₅alkyl,C₃-C₇cycloalkyl, aryl, or aralkyl;

t and v are independently 1, 2, or 3; and

x represents independently for each occurrence 0, 1, 2, or 3.

In certain embodiments, the cancer is a solid tumor. In certain otherembodiments, the cancer is brain cancer, bladder cancer, breast cancer,cervical cancer, colon cancer, colorectal cancer, endometrial cancer,esophageal cancer, leukemia, lung cancer, liver cancer, melanoma,ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renalcancer, stomach cancer, testicular cancer, or uterine cancer. In yetother embodiments, the cancer is a vascularized tumor, squamous cellcarcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma,neuroblastoma, sarcoma (e.g., an angiosarcoma or chondrosarcoma), larynxcancer, parotid cancer, bilary tract cancer, thyroid cancer, acrallentiginous melanoma, actinic keratoses, acute lymphocytic leukemia,acute myeloid leukemia, adenoid cycstic carcinoma, adenomas,adenosarcoma, adenosquamous carcinoma, anal canal cancer, anal cancer,anorectum cancer, astrocytic tumor, bartholin gland carcinoma, basalcell carcinoma, biliary cancer, bone cancer, bone marrow cancer,bronchial cancer, bronchial gland carcinoma, carcinoid,cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma,chronic lymphocytic leukemia, chronic myeloid leukemia, clear cellcarcinoma, connective tissue cancer, cystadenoma, digestive systemcancer, duodenum cancer, endocrine system cancer, endodermal sinustumor, endometrial hyperplasia, endometrial stromal sarcoma,endometrioid adenocarcinoma, endothelial cell cancer, ependymal cancer,epithelial cell cancer, Ewing's sarcoma, eye and orbit cancer, femalegenital cancer, focal nodular hyperplasia, gallbladder cancer, gastricantrum cancer, gastric fundus cancer, gastrinoma, glioblastoma,glucagonoma, heart cancer, hemangiblastomas, hemangioendothelioma,hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatobiliarycancer, hepatocellular carcinoma, Hodgkin's disease, ileum cancer,insulinoma, intaepithelial neoplasia, interepithelial squamous cellneoplasia, intrahepatic bile duct cancer, invasive squamous cellcarcinoma, jejunum cancer, joint cancer, Kaposi's sarcoma, pelviccancer, large cell carcinoma, large intestine cancer, leiomyosarcoma,lentigo maligna melanomas, lymphoma, male genital cancer, malignantmelanoma, malignant mesothelial tumors, medulloblastoma,medulloepithelioma, meningeal cancer, mesothelial cancer, metastaticcarcinoma, mouth cancer, mucoepidermoid carcinoma, multiple myeloma,muscle cancer, nasal tract cancer, nervous system cancer,neuroepithelial adenocarcinoma nodular melanoma, non-epithelial skincancer, non-Hodgkin's lymphoma, oat cell carcinoma, oligodendroglialcancer, oral cavity cancer, osteosarcoma, papillary serousadenocarcinoma, penile cancer, pharynx cancer, pituitary tumors,plasmacytoma, pseudosarcoma, pulmonary blastoma, rectal cancer, renalcell carcinoma, respiratory system cancer, retinoblastoma,rhabdomyosarcoma, sarcoma, serous carcinoma, sinus cancer, skin cancer,small cell carcinoma, small intestine cancer, smooth muscle cancer, softtissue cancer, somatostatin-secreting tumor, spine cancer, squamous cellcarcinoma, striated muscle cancer, submesothelial cancer, superficialspreading melanoma, T cell leukemia, tongue cancer, undifferentiatedcarcinoma, ureter cancer, urethra cancer, urinary bladder cancer,urinary system cancer, uterine cervix cancer, uterine corpus cancer,uveal melanoma, vaginal cancer, verrucous carcinoma, VIPoma, vulvacancer, well differentiated carcinoma, or Wilms tumor.

In certain other embodiments, the cancer is non-Hodgkin's lymphoma, suchas a B-cell lymphoma or a T-cell lymphoma. In certain embodiments, thenon-Hodgkin's lymphoma is a B-cell lymphoma, such as a diffuse largeB-cell lymphoma, primary mediastinal B-cell lymphoma, follicularlymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginalzone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma,Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, orprimary central nervous system (CNS) lymphoma. In certain otherembodiments, the non-Hodgkin's lymphoma is a T-cell lymphoma, such as aprecursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma,cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma,extranodal natural killer/F-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplasticlarge cell lymphoma, or peripheral T-cell lymphoma.

The therapeutic methods may optionally comprise exposing the patient toradiation. One exemplary form of radiation is gamma rays, such as thoseproduced from a ¹³⁷Cs source. The amount of radiation can be optimizedfor particular conditions. In certain embodiments, the quantity ofradiation applied to the patient is at least about 2 Gy, about 5 Gy,about 10 Gy, or about 15 Gy.

In addition, the therapeutic methods may optionally compriseadministering a chemotherapeutic agent to the patient. Exemplarychemotherapeutic agents include azacitidine, azathioprine, bleomycin,carboplatin, capecitabine, carmustine, cisplatin, chlorambucil,cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel,doxifluridine, doxorubicin, epirubicin, epothilone, etoposide,fluorouracil, fulvestrant, gemcitabine, hydroxyurea, idarubicin,imatinib, lomustine, mechlorethamine, mercaptopurine, methotrexate,mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, procarbazine,raloxifene, teniposide, temozolomide, thiotepa, tioguanine, tamoxifen,toremifene, valrubicin, vinblastine, vincristine, vindesine,vinorelbine, and pharmaceutically acceptable salts thereof.

In certain embodiments, the patient is a human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Section II, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaII, a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula II, a compound of FormulaIA, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula IA.

The description above describes multiple embodiments relating to methodsof treating various disorders using certain organonitro thioethercompounds. The patent application specifically contemplates allcombinations of the embodiments. For example, the invention contemplatesmethods for treating cancer (such as breast cancer, leukemia, orprostate cancer) by administering a therapeutically effective amount ofa compound of Formula IA wherein A¹ is N, R¹ is hydrogen, R⁴ is—CH₂C(H)(X¹)X², and p is 1.

In certain embodiments, the compound is

or a pharmaceutically acceptable salt thereof. In certain otherembodiments, the compound is

or a pharmaceutically acceptable salt thereof. In another embodiment,the compound is

or a pharmaceutically acceptable salt thereof. In one embodiment, thecompound is

or a pharmaceutically acceptable salt thereof. In certain otherembodiments, the compound is

or a pharmaceutically acceptable salt thereof. In certain otherembodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound is

or a pharmaceutically acceptable salt thereof. In certain otherembodiments, the compound is

or a pharmaceutically acceptable salt thereof.

Combination Therapy

As indicated above, invention embraces combination therapy, whichincludes the administration of an organonitro thioether compounddescribed herein (such as compound of Formula I, II or IA) and a secondagent as part of a specific treatment regimen intended to provide thebeneficial effect from the co-action of these therapeutic agents. Thebeneficial effect of the combination may include pharmacokinetic orpharmacodynamic co-action resulting from the combination of therapeuticagents. Administration of these therapeutic agents in combinationtypically is carried out over a defined time period (e.g., hours or daysdepending upon the combination selected). The combination therapy mayinvolve administration of two or more of these therapeutic agents aspart of separate monotherapy regimens that result in the combinations ofthe present invention. Combination therapy also includes administrationof these therapeutic agents in a sequential manner, that is, whereineach therapeutic agent is administered at a different time, as well asadministration of these therapeutic agents, or at least two of thetherapeutic agents, in a substantially simultaneous manner.Substantially simultaneous administration can be accomplished, forexample, by administering to the subject a single capsule having a fixedratio of each therapeutic agent or in multiple, single capsules for eachof the therapeutic agents. Sequential or substantially simultaneousadministration of each therapeutic agent can be effected by anyappropriate route including, but not limited to, oral routes,intravenous routes, intramuscular routes, and direct absorption throughmucous membrane tissues.

It is understood that the therapeutic agents can be administered by thesame route or by different routes. For example, a first therapeuticagent of the combination selected may be administered by pulmonaryadministration while the other therapeutic agent(s) of the combinationmay be administered orally. Alternatively, for example, all therapeuticagents may be administered orally or all therapeutic agents may beadministered by pulmonary administration.

Accordingly, in certain embodiments, one or more of the methodsdescribed herein above further comprise administering to the patient atherapeutically effective amount of a second therapeutic agent. Incertain embodiments, the second therapeutic agent is, for example,adenosine, an antimicrobial compound, an aldosterone antagonist, analpha-adrenergic receptor antagonist, a β-adrenergic agonist, ananti-allergic compound, an anti-diabetic compound, ananti-hyperlipidemic drug, an anti-tussive compound, an angiotensin IIantagonist, an angiotensin-converting enzyme (ACE) inhibitor, anantioxidant, an antithrombotic, a vasodilator drug, a β-adrenergicantagonist, a bronchodilator, a calcium channel blocker, a diuretic, anendothelin antagonist, an expectorant, a hydralazine compound, aH2-receptor antagonist, a neutral endopeptidase inhibitor, anonsteroidal antiinflammatory compound (NSAID), a phosphodiesteraseinhibitor, a potassium channel blocker, a platelet reducing agent, aproton pump inhibitor, a renin inhibitor, a selective cyclooxygenase-2(COX-2) inhibitor, or a steroid. In certain other embodiments, thesecond therapeutic agent is selected from the group consisting of anantimicrobial compound, a β-adrenergic agonist, an anti-allergiccompound, an anti-tussive compound, an antioxidant, a bronchodilator, anexpectorant, a nonsteroidal antiinflammatory compound (NSAID), aphosphodiesterase inhibitor, a selective cyclooxygenase-2 (COX-2)inhibitor, or a steroid.

IV. PHARMACEUTICAL COMPOSITIONS

The invention provides pharmaceutical compositions comprising apharmaceutical carrier and an organonitro thioether compound describedherein, such as a compound of Formula I or II, which as described above,Formula I is represented by:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

A¹ is N or —C(R⁵)—;

A² is —C(O)— or —(C(R⁶)₂)_(x)C(O)(C(R⁶)₂)_(x)—;

R¹ is C₁-C₅alkyl;

R² and R³ each represent independently for each occurrence hydrogen orC₁-C₅alkyl; or R² and R³ are taken together with the carbon atom towhich they are attached to form a carbocyclic ring;

R⁴ is C₁-C₅alkyl substituted with one X¹ group and one X² group; whereinX¹ is —N(R⁷)(R⁸), —N(R⁷)C(O)—C₁-C₅alkyl, —N(R⁷)C(O)—C₃-C₇cycloalkyl,—N(R⁷)C(O)-aryl, —N(R⁷)C(O)-aralkyl, or—N(R⁷)C(O)—(C₁-C₅alkylene)-C(H)[N(R⁷)(R⁸)]—CO₂R⁹; and X² is —CO₂R¹⁰ or—C(O)N(R⁷)—(C₁-C₅alkylene)-CO₂R¹⁰;

R⁵ is hydrogen or C₁-C₅alkyl;

R⁶ represents independently for each occurrence C₁-C₆alkyl,C₁-C₅haloalkyl, aryl, or aralkyl;

R⁷ and R⁸ each represent independently for each occurrence hydrogen orC₁-C₅alkyl; or R⁷ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocyclic ring;

R⁹ and R¹⁰ each represent independently hydrogen, C₁-C₅alkyl,C₃-C₇cycloalkyl, aryl, or aralkyl;

n, p, and t are independently 1, 2, or 3; and

m and x each represent independently for each occurrence 0, 1, 2, or 3;and Formula II is represented by:

or a pharmaceutically acceptable salt or solvate thereof: wherein:

A¹ is —N(R⁵)— or —C(R²)(R³)—;

A² is —C(O)— or —(C(R⁶)₂)_(x)C(O)(C(R⁶)₂)_(x)—;

R¹ is C₁-C₅alkyl or C₃-C₇cycloalkyl;

R² and R³ each represent independently for each occurrence hydrogen orC₁-C₅alkyl; or R² and R³ are taken together with the carbon atom towhich they are attached to form a carbocyclic ring;

R⁴ is C₁-C₅alkyl substituted with one X¹ group and one X² group; whereinX¹ is —N(R⁷)(R⁸), —N(R⁷)C(O)—C₁-C₅alkyl, —N(R⁷)C(O)—C₃-C₇cycloalkyl,—N(R⁷)C(O)-aryl, —N(R⁷)C(O)-aralkyl, or—N(R⁷)C(O)—(C₁-C₅alkylene)-C(H)[N(R⁷)(R⁸)]—CO₂R⁹; and X² is —CO₂R¹⁰ or—C(O)N(R⁷)—(C₁-C₅alkylene)-CO₂R¹⁰;

R⁵ is hydrogen or C₁-C₅alkyl;

R⁶ represents independently for each occurrence C₁-C₅alkyl,C₁-C₅haloalkyl, aryl, or aralkyl;

R⁷ and R⁸ each represent independently for each occurrence hydrogen orC₁-C₅alkyl; or R⁷ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocyclic ring;

R⁹ and R¹⁰ each represent independently hydrogen, C₁-C₅alkyl,C₃-C₇cycloalkyl, aryl, or aralkyl;

t and v are independently 1, 2, or 3; and

x represents independently for each occurrence 0, 1, 2, or 3.

In certain embodiments, the organonitro thioether compound is defined byone or more of the particular embodiments described above in Section II,such as where the organonitro thioether compound is a compound FormulaI, A¹ is N, R² and R³ are hydrogen, m is 0, and n is 2.

In certain embodiments, the pharmaceutical compositions preferablycomprise a therapeutically-effective amount of one or more of theorganonitro thioether compounds described above, formulated togetherwith one or more pharmaceutically acceptable carriers (additives) and/ordiluents. As described in detail below, the pharmaceutical compositionsof the present invention may be specially formulated for administrationin solid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (aqueous or non-aqueoussolutions or suspensions), tablets (e.g., those targeted for buccal,sublingual, and/or systemic absorption), boluses, powders, granules,pastes for application to the tongue; (2) parenteral administration by,for example, subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; (3) topical application, for example, asa cream, ointment, or a controlled-release patch or spray applied to theskin; (4) intravaginally or intrarectally, for example, as a pessary,cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8)nasally.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient that can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of one hundred percent, this amount will range from about0.1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders a compound of the present invention orallybioavailable.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug administered by subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material having poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of aparenterally-administered drug form is accomplished by dissolving orsuspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

Organonitro thioether compounds and/or pharmaceutical compositionsthereof may also be administered directly to the lung by inhalation. Foradministration by inhalation, organonitro thioether compounds and/orpharmaceutical compositions thereof may be conveniently delivered to thelung by a number of different devices. For example, a Metered DoseInhaler (“MDI”), which utilizes canisters that contain a suitable lowboiling propellant, (e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or anyother suitable gas) may be used to deliver organonitro thioethercompounds and/or pharmaceutical compositions thereof directly to thelung.

Alternatively, a Dry Powder Inhaler (“DPI”) device may be used toadminister an organonitro thioether compound and/or pharmaceuticalcomposition thereof to the lung. DPI devices typically use a mechanismsuch as a burst of gas to create a cloud of dry powder inside acontainer, which may then be inhaled by the patient, and are well knownin the art. A popular variation is the multiple dose DPI (“MDDPI”)system, which allows for the delivery of more than one therapeutic dose.MDDPI devices are commercially available from a number of pharmaceuticalcompanies (e.g., Schering Plough, Madison, N.J.). For example, capsulesand cartridges of gelatin for use in an inhaler or insufflator may beformulated containing a powder mix of an organonitro thioether compoundand/or pharmaceutical composition thereof and a suitable powder basesuch as lactose or starch for these systems.

Another type of device that may be used to deliver a compound and/orpharmaceutical composition thereof to the lung is a liquid spray devicesupplied, for example, by Aradigm Corporation, Hayward, Calif. Liquidspray systems use extremely small nozzle holes to aerosolize liquid drugformulations that may then be directly inhaled into the lung.

In some embodiments, a nebulizer is used to deliver an organonitrothioether compound and/or pharmaceutical composition thereof to thelung. Nebulizers create aerosols from liquid drug formulations by using,for example, ultrasonic energy to form fine particles that may bereadily inhaled (see e.g., Verschoyle et al., British J. Cancer, 1999,80, Suppl. 2, 96). Examples of nebulizers include devices supplied bySheffield Pharmaceuticals. St. Louis. Mo. (see, e.g., Armer et al., U.S.Pat. No. 5,954,047; van der Linden et al., U.S. Pat. No. 5,950,619; vander Linden et al., U.S. Pat. No. 5,970,974) and Batelle PulmonaryTherapeutics, Columbus, Ohio.

In other embodiments, an electrohydrodynamic (“EHID”) aerosol device isused to deliver an organonitro thioether compound and/or pharmaceuticalcomposition thereof to the lung of a patient. EHD aerosol devices useelectrical energy to aerosolize liquid drug solutions or suspensions(see e.g., Noakes et al., U.S. Pat. No. 4,765,539). The electrochemicalproperties of the formulation may be important parameters to optimizewhen delivering an organonitro thioether compound and/or pharmaceuticalcomposition thereof to the lung with an EHID aerosol device and suchoptimization is routinely performed by one of skill in the art. EHDaerosol devices may more efficiently deliver drugs to the lung thanexisting pulmonary delivery technologies.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administrations are preferred.

The phrase “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and include, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal, and intrasternal injection and infusion.

The phrases “systemic administration.” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Preferably, the compounds areadministered at about 0.01 mg/kg to about 200 mg/kg, more preferably atabout 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5mg/kg to about 50 mg/kg. When the compounds described herein areco-administered with another agent (e.g., as sensitizing agents), theeffective amount may be less than when the agent is used alone.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. Preferred dosing is one administrationper day.

V. KITS FOR USE IN MEDICAL APPLICATIONS

Another aspect of the invention provides a kit for treating a disorder.The kit comprises: i) instructions for treating cancer, such as a cancerselected from the group consisting of brain cancer, bladder cancer,breast cancer, cervical cancer, colon cancer, colorectal cancer,endometrial cancer, esophageal cancer, leukemia, lung cancer, livercancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer,rectal cancer, renal cancer, stomach cancer, testicular cancer, anduterine cancer; and ii) an organonitro thioether compound describedherein, such as a compound of Formula I or II. The kit may comprise oneor more unit dosage forms containing an amount of an organonitrothioether compound described herein, such as a compound of Formula I orII, that is effective for treating said cancer.

The description above describes multiple aspects and embodiments of theinvention, including organonitro thioether compounds, compositionscomprising organonitro thioether compounds, methods of using theorganonitro thioether compound, and kits. The patent applicationspecifically contemplates all combinations and permutations of theaspects and embodiments. For example, the invention contemplatestreating cancer in a human patient by administering a therapeuticallyeffective amount of a compound of Formula IA. Further, for example, theinvention contemplates a kit for treating cancer, the kit comprisinginstructions for treating cancer (such as breast cancer, leukemia, orprostate cancer) and ii) an organonitro thioether compound describedherein, such as a compound of Formula IA.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1 Preparation of ABDNAZ-Cysteine (ABDNAZ-CYS)

A solution of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ, 1340mg, 5.00 mmol) in cold methanol (30 mL) was added dropwise to a stirredsolution of cysteine (610 mg, 5.03 mmol) and sodium acetate (420 mg,5.12 mmol) in reverse osmosis water (10 mL) and methanol (10 mL) over 30minutes and maintained at 0-5° C. in a reaction flask. When the additionwas complete, a substantial amount of white solid had separated and thereaction flask was closed and maintained at −10° C. for 2 hours. Thewhite solid was separated by filtration, washed with cooled methanol(−10° C.) and then dried at 60° C. to give 910 mg of the title compoundas a white solid having a melting point of 150-152° C.

The filtrate and wash was then evaporated to dryness under reducedpressure and the white residue treated with ethanol (10 mL), the flasksealed and allowed to stand for 36 hours. The resultant white solid wasremoved by filtration, washed with ethanol and dried at 60° C. to give400 mg of the title compound as a white solid having a melting point of151-153° C. The infrared spectra of the two products were identical andthe combined yield of 1310 mg represented an 85% yield of product. Thecombined products were recrystallized from water/ethanol (1 to 4) with88% recovery to give product with an infrared spectrum identical to theproduct before recrystallization, a single spot on TLC and mp 151-153°C. FTIR (KBr press): 3438.3, 3015.9, 2076.0, 1670.1, 1634.9, 1582.1,1446.5, 1388.0, 1337.6, and 1304.8 cm⁻¹.

ABDNAZ can be prepared as described in U.S. Pat. No. 7,507,842, which ishereby incorporated by reference.

Example 2 Preparation of ABDNAZ-Glutathione

A 40 mL vial equipped with a magnetic stirrer was charged with methanol(20 mL) and deionized water (5 mL). L-Glutathione (0.50 g, 1.63 mmole)was added followed by sodium acetate (0.17 g, 2.07 mmole). The mixturewas stirred until the solids dissolved.2-Bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ, 0.43 g, 1.60mmole) was then added to the solution and the reaction was stirred atroom temperature for 18 hours. The reaction mixture was then filteredand the solids were washed with methanol (10 mL). The solids were thendried in a vacuum oven at 50° C. for 20 hours to provide the titlecompound.

Example 3 Preparation of(R)-2-Amino-3-[2-(3,3-Dinitro-Azetidin-1-yl)-2-Oxoethylsulfanyl]-PropionicAcid Methyl Ester Hydrochloride

A solution of ABDNAZ (850, 3.17 mmol) in cold (0° C.) methanol (35 mL)was added dropwise to a cold (0° C.) stirred solution of N-Boc-cysteinemethyl ester (785 mg, 3.23 mmol) and sodium acetate (265 mg, 3.23 mmol)in methanol (15 mL) and HPLC grade water (15 mL) over 30 mins. After 2hours, thin-layer chromatography (TLC) showed complete conversion. Themixture was concentrated to dryness under reduced pressure and ethylacetate was added to the residue and the mixture filtered through celiteand the filtrate concentrated under reduced pressure. The crude productwas treated with 4 N HCl in dioxane (35 mL) and the resulting mixturewas stirred overnight at room temperature. Then, the mixture wasconcentrated under reduced pressure. Ethyl acetate was added and thesolid was filtered and further dried under vacuum to yield 660 mg (65%for two steps) of the title compound as a white solid. ¹H NMR (200 MHz,D₂O) δ 3.09 (dd, 1H, J=8.0, 15.4 Hz), 3.26 (dd, 1H, J=4.8, 15.4 Hz),3.36 (s, 3H), 3.75 (s, 3H), 4.32 (dd, 1H, J=4.8, 8.0 Hz), 4.89 (bs, 2H),5.09 (s, 2H), 5.17 (bs, 2H), LC/MS (M+H=323). The purity was checkedusing LC/MS using Phenomenex Luna 3μ C8 (2) 100A column using water with0.1% TFA and acetonitrile with 0.1% as mobile phase (30-90% acetonitrile@1.0 mL/min). Retention time=0.45 mins; Area %=97.9%.

Example 4 Preparation of (R)-Methyl2-Acetamido-3-(2-(3,3-Dinitroazetidin-1-yl)-2-Oxoethylthio)Propanoate

A solution of ABDNAZ (474 mg, 1.77 mmol) in cold (0° C.) methanol (20mL) was added dropwise to a cold (0° C.) stirred solution ofN-acetylcysteine methyl ester (320 mg, 1.80 mmol) and sodium acetate(148 mg, 1.80 mmol) in methanol (5 mL) and HPLC grade water (5 mL) over30 mins. After 2 hours, TLC showed complete conversion. The mixture wasconcentrated to dryness under reduced pressure and ethyl acetate wasadded to the residue and the mixture filtered through celite. Thefiltrate was concentrated under reduced pressure and the residuepurified by column chromatography on silica gel (using 50% ethyl acetatein hexanes to pure ethyl acetate as eluent) to yield 515 mg (80%) of thetitle compound as a white foam. ¹H NMR (200 MHz, CDCl₃) δ 2.04 (s, 3H),2.97 (dd, 1H, J=7.4, 14.8 Hz), 3.19 (dd, 1H, J=4.8, 14.8 Hz), 3.24 (s,2H), 3.78 (s, 3H), 5.13-4.83 (m, 5H), 6.48 (d, 1H, J=7.4 Hz). LC/MS(M+H=365 and M+Na=387). The purity was checked using LC/MS usingPhenomenex Luna 3μ C8 (2) 100A column using water with 0.1% TFA andacetonitrile with 0.1% as mobile phase (30-90% acetonitrile @1.0mL/min). Retention time=0.87 mins; Area %=100%.

Example 5 Preparation of(R)-2-Acetamido-3-(2-(3,3-Dinitroazetidin-1-yl)-2-Oxoethylthio)PropanoicAcid

(R)-Methyl2-acetamido-3-(2-(3,3-dinitroazetidin-1-yl)-2-oxoethylthio)propanoate(1.02 g, 2.80 mmol) was dissolved in methanol (50 mL) with stirring andthe mixture cooled to 0° C. Then, LiOH (0.5 M, 8.40 mL) was addeddropwise to the reaction mixture via a syringe and the resulting yellowmixture stirred until TLC showed complete conversion (2.5 hours). Next,the reaction mixture was diluted with water, cooled to 0° C. andacidified to pH=2 with a 50% HCl solution. Then, the reaction mixturewas extracted with ethyl acetate (×2) and the extracts were dried overNa₂SO₄, filtered and concentrated under reduced pressure to provide aresidue that was purified by column chromatography using silica gel and30% MeOH in EtOAc as eluent to provide the title compound 625 mg (64%)as a white solid. ¹H NMR (200 MHz, DMSO-d⁶) δ 1.85 (s, 3H), 2.81 (dd,1H, J=8.4, 13.6 Hz), 3.04 (dd, 1H, J=4.8, 13.6 Hz), 3.33 (s, 2H),4.41-4.35 (m, 1H), 4.80 (s, 2H), 5.13 (s, 2H), 8.20 (d, 1H, J=8.0 Hz).LC/MS (M+H=351). The purity was checked using LC/MS using PhenomenexLuna 3μ C8 (2) 100A column using water with 0.1% TFA and acetonitrilewith 0.1% as mobile phase (30-90% acetonitrile @1.0 mL/min). Retentiontime=0.60 mins; Area %=97.6%.

Example 6 Anti-Cancer Assay

Mice with SCC VII tumors were treated with Compound 1, which has thefollowing chemical structure.

Experimental procedures and results are provided below.

Part I: Experimental Procedure Treatment Composition:

The Treatment Composition was Compound 1 in a water/DMSO carrier. TheTreatment Composition was prepared by dissolving 2.3 mg of Compound 1 in0.1 mL of DMSO and mixing the resultant solution with 1.9 mL, of waterto provide a solution containing 1.15 mg/mL of Compound 1. Theconcentration of dimethylsulfoxide (DMSO) in the Treatment Compositionwas 5%.

Study Procedures:

Male C31H mice were obtained from Charles River Laboratories andmaintained under specific pathogen-free conditions. Mice were housedfive animals per cage and autoclaved food and water was provided adlibitum. Cages were located in rooms having a temperature of 65±2degrees Fahrenheit, a humidity of 50%±5%, and a 12-hour day-and-nightlight cycle. Mice were 7-8 weeks old, with a body weight in the range of22-25 grams, at the time inoculated with tumor cells.

Mice were inoculated subcutaneously with 5×10⁵ SCCVII tumor cells in0.05 mL Hank's solution on the back. Ten days after tumor implantation,treatment was initiated (Day 0) by administering the TreatmentComposition by intraperitoneal injection every other day (i.e., q.o.d onDays 0, 2, and 4) for 3 doses total. The length and width of the tumorswere measured with calipers immediately before treatment and three timesa week thereafter until the tumor volume reached at least four times(4×) the original pre-treatment volume. Tumor volume (mm³) wascalculated according to the formula:

Tumor Volume=π/6×length×width²

Part II: Results

Tumors in mice that received the Treatment Composition were smaller thantumors in mice that did not receive the Treatment Composition (i.e., thecontrol). Experimental data showing tumor volume in treated anduntreated (control) mice are provided in FIG. 1.

Example 7 Toxicity Evaluation in Healthy Rats

Compound 1 was administered to healthy rats and the rats were evaluatedfor evidence of toxic side effects due to Compound 1. Experimentalprocedures and results are described below. The results indicate that nosignificant toxicity was observed in rats receiving Compound 1.

Part I: Experimental Procedure

Two groups of 3 male rats each were given a 100 or 300 mg/kg dose ofCompound 1 prepared in 0.9% saline solution. A third group of 3 ratswere given saline alone. Doses were delivered via a femoral vein. The100 mg/kg dose was delivered using a 10 mg/mL solution at a dose volumeof 10 mL/kg and an infusion rate of 15 mL/hr. The 300 mg/kg dose wasdelivered using a 20 mg/mL solution at a dose volume of 15 mL/kg and aninfusion rate of 15 mL/hr. Animals were observed for 24 hours,necropsied (and the pleural and abdominal cavities were observedgrossly), and the lungs collected for possible microscopic evaluation.

Part II: Results

No notable clinical observations were found in rats that received the100 mg/kg dose of Compound 1. Rats that received the 300 mg/kg dose ofCompound 1 were observed to be pale during the first 3 hours post dose.There were no gross changes in the lungs of rats that receivedCompound 1. Mottled kidneys were observed in most rats that receivedCompound 1, but further evaluation would be required to determine ifthis observation has significance for measuring the toxicity of Compound1.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

What is claimed is: 1-53. (canceled)
 54. A method of treating cancer ina human patient, comprising administering to a human patient in needthereof a therapeutically effective amount of a pharmaceuticalcomposition comprising an organonitro compound of Formula I-A to treatthe cancer, wherein Formula I-A is represented by:

or a pharmaceutically acceptable salt thereof, wherein: A¹ is N; R¹represents independently for each occurrence hydrogen or methyl; R⁴ isC₁-C₅alkyl substituted with one X¹ group and one X² group; wherein X¹ is—NH₂, —N(H)C(O)—C₁-C₅alkyl or —N(H)C(O)—(C₁-C₅alkylene)-C(H)NH₂)—CO₂H;and X² is —CO₂H, —CO₂—C₁-C₅alkyl, or —C(O)N(H)CH₂CO₂H; and p representsindependently for each occurrence 1 or
 2. 55. The method of claim 54,wherein the cancer is a solid tumor.
 56. The method of claim 54, whereinthe cancer is brain cancer, bladder cancer, breast cancer, cervicalcancer, colon cancer, colorectal cancer, endometrial cancer, esophagealcancer, leukemia, lung cancer, liver cancer, melanoma, ovarian cancer,pancreatic cancer, prostate cancer, rectal cancer, renal cancer, stomachcancer, testicular cancer, or uterine cancer.
 57. The method of claim56, further comprising exposing the cancer to radiation.
 58. (canceled)59. (canceled)
 60. The method of claim 54, wherein the cancer is braincancer, bladder cancer, breast cancer, or cervical cancer.
 61. Themethod of claim 54, wherein the cancer is colon cancer or colorectalcancer.
 62. The method of claim 54, wherein the cancer is leukemia. 63.The method of claim 54, wherein the cancer is lung cancer, liver cancer,melanoma, ovarian cancer, pancreatic cancer, or prostate cancer.
 64. Themethod of claim 54, wherein the cancer is rectal cancer, renal cancer,testicular cancer, or uterine cancer.
 65. The method of claim 60,wherein R⁴ is


66. The method of claim 61, wherein R⁴ is


67. The method of claim 62, wherein R⁴ is


68. The method of claim 63, wherein R⁴ is


69. The method of claim 64, wherein R⁴ is


70. The method of claim 56, wherein the organonitro compound is

or a pharmaceutically acceptable salt thereof.
 71. The method of claim60, wherein the organonitro compound is

or a pharmaceutically acceptable salt thereof.
 72. The method of claim61, wherein the organonitro compound is

or a pharmaceutically acceptable salt thereof.
 73. The method of claim62, wherein the organonitro compound is

or a pharmaceutically acceptable salt thereof.
 74. The method of claim63, wherein the organonitro compound is

or a pharmaceutically acceptable salt thereof.
 75. The method of claim64, wherein the organonitro compound is

or a pharmaceutically acceptable salt thereof.